This invention relates to a process for resolving (.+-.)-cis-1-ethyl-1,3,4,9-tetrahydro-4-(phenylmethyl)pyrano[3,4-b]indole- 1-acetic acid using brucine and preferential crystallization of the enriched free acid to obtain the corresponding (1S,4R)-enantiomer.
(.+-.)-cis-1-Ethyl-1,3,4,9-tetrahydro-4-(phenylmethyl)pyrano[3,4-b]indole-1 -acetic acid, an optically inactive racemic mixture, is known generically as pemedolac, and as an analgesic agent described in Katz et al U.S. Pat. No. 4,670,462.
Pemedolac possesses the 4-(phenylmethyl) group and the 1-acetic acid on the same side of a plane containing the flat indole nucleus. The molecule is asymetric and is obtained as a mixture of two optical isomers. A. H. Katz, C. A. Demerson, et al., J. Med. Chem., 31, 1244-1250 (1988) describes the resolution of (.+-.)-pemedolac via the chromatographic separation of its diastereomeric esters with [(1S)-endo]-(-)-borneol, followed by hydrolysis. Pemedolac is a potent analgesic agent and the analgesic effect was found to reside in (+)-pemedolac, the (1S,4R)-enantiomer. The absolute configuration was assigned on the basis of a crystallographic analysis of the (S)-(-)-borneol ester.
The present process avoids the tedious and expensive chromatographic separation previously reported, and provides the eutomer, the (1S,4R)-enantiomer, in high yield and in a commercially feasible operation.